Department of Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, United States.
Invest Ophthalmol Vis Sci. 2019 Sep 3;60(12):3740-3751. doi: 10.1167/iovs.19-27212.
Chronic oxidative stress is an important mechanism of disease in aging disorders. We do not have a good model to recapitulate AMD and other retinal disorders in which chronic oxidative stress plays an important role. We hypothesized that mice with a combined deficiency in superoxide dismutase 1 (Sod1), DJ-1 (Park-7), and Parkin (Prkn) (triple knock out, TKO) would have an increased level of chronic oxidative stress in the retina, with anatomic and functional consequences just with aging.
Eyes of TKO and B6J control mice were (1) monitored with optical coherence tomography (OCT) and electroretinography (ERG) over time, and (2) collected for oxidative marker protein analysis by ELISA or immunohistochemistry and for transmission electron microscopy studies.
TKO mice developed qualitative disruptions in outer retinal layers in OCT by 3 months, increased accumulation of fundus spots and subretinal microglia by 6 months of age, significant retinal thinning by 9 months, and decreased ERG signal by 12 months. Furthermore, we found increased accumulation of the oxidative marker malondialdehyde (MDA) in the retina and increased basal laminal deposits (BLD) and mitochondria number and size in the retinal pigment epithelium of aging TKO mice.
TKO mice can serve as a platform to study retinal diseases that involve chronic oxidative stress, including macular degeneration, retinal detachment, and ischemic retinopathies. In order to model each of these diseases, additional disease-specific catalysts or triggers could be superimposed onto the TKO mice. Such studies could provide better insight into disease mechanisms and perhaps lead to new therapeutic approaches.
慢性氧化应激是衰老相关疾病的重要发病机制。我们目前还没有一个很好的模型可以重现慢性氧化应激发挥重要作用的 AMD 和其他视网膜疾病。我们假设，超氧化物歧化酶 1（Sod1）、DJ-1（Park-7）和 Parkin（Prkn）联合缺失（三敲除，TKO）的小鼠视网膜内会出现慢性氧化应激水平升高，即使在衰老过程中也会出现解剖和功能后果。
（1）通过光学相干断层扫描（OCT）和视网膜电图（ERG）随时间监测 TKO 和 B6J 对照小鼠的眼睛；（2）通过 ELISA 或免疫组织化学法进行氧化标志物蛋白分析，并通过透射电子显微镜研究收集。
TKO 小鼠在 3 个月时通过 OCT 出现外视网膜层的定性破坏，在 6 个月时出现眼底斑点和视网膜下小胶质细胞的积累增加，在 9 个月时出现明显的视网膜变薄，在 12 个月时出现 ERG 信号降低。此外，我们发现衰老 TKO 小鼠视网膜内 MDA（氧化标志物）的积累增加，以及视网膜色素上皮内基底膜沉积（BLD）和线粒体数量及大小增加。
TKO 小鼠可作为研究涉及慢性氧化应激的视网膜疾病的平台，包括黄斑变性、视网膜脱离和缺血性视网膜病变。为了对这些疾病中的每一种进行建模，可以将特定于疾病的催化剂或触发物叠加到 TKO 小鼠上。此类研究可以深入了解疾病机制，并可能为新的治疗方法提供思路。
